Investigational New Drugs

, Volume 34, Issue 2, pp 159–167 | Cite as

The novel pyrrolo-1,5-benzoxazepine, PBOX-15, synergistically enhances the apoptotic efficacy of imatinib in gastrointestinal stromal tumours; suggested mechanism of action of PBOX-15

  • Paula Kinsella
  • Lisa M. Greene
  • Sandra A. Bright
  • Jade K. Pollock
  • Stefania Butini
  • Giuseppe Campiani
  • Sebastian Bauer
  • D. Clive Williams
  • Daniela M. Zisterer


The C-KIT receptor tyrosine kinase is constitutively activated in the majority of gastrointestinal stromal tumours (GIST). Imatinib (IM) a selective inhibitor of C-KIT, is indicated for the treatment of KIT-positive unresectable and/or metastatic GIST, and has tripled the survival time of patients with metastatic GIST. However, the majority of patients develop IM-resistance and progress. Although IM elicits strong antiproliferative effects, it fails to induce sufficient levels of apoptosis; acquired IM-resistance and disease recurrence remain an issue, a more effective drug treatment is greatly needed. We examined the effect of a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-15 in combination with IM on GIST cells. PBOX-15 decreased viability and in combination with IM synergistically enhanced apoptosis in both IM-sensitive and IM-resistant GIST cells, decreased the anti-apoptotic protein Mcl-1, and enhanced activation of pro-caspase-3 and PARP cleavage. The combination treatment also led to an enhanced inhibition of C-KIT-phosphorylation and inactivation of C-KIT-dependent signalling in comparison to either drug alone; CDC37, a key regulator of C-KIT in GIST was also dramatically decreased. Furthermore, PBOX-15 reduced CKII expression, an enzyme which regulates the expression of CDC37. In conclusion, our findings indicate the potential of PBOX-15 to improve the apoptotic response of IM in GIST cells and provide a more effective treatment option for GIST patients.


Gastrointestinal Imatinib Microtubules CKIT CDC37 CKII 



We would like to thank Novartis Pharma AG, Basel, Switzerland for their kind donation of imatinib. We would also like to thank Dr. Jonathan Fletcher for his initial advice with this project.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10637_2016_331_MOESM1_ESM.pptx (127 kb)
Supp Fig.1 Imatinib/PBOX-15 gives a small amount of PARP cleavage in GIST-T1. Cells were treated with vehicle (Veh), imatinib (0.16 μM), PBOX-15 (0.6 μM) or combination for 24 h in GIST-T1 cells, cell lysates were prepared for western blot analysis. β-actin expression was measured as a loading control. Results are representative of three separate experiments. (PPTX 126 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Paula Kinsella
    • 1
  • Lisa M. Greene
    • 1
  • Sandra A. Bright
    • 1
  • Jade K. Pollock
    • 1
  • Stefania Butini
    • 2
  • Giuseppe Campiani
    • 2
  • Sebastian Bauer
    • 3
  • D. Clive Williams
    • 1
  • Daniela M. Zisterer
    • 1
  1. 1.School of Biochemistry and Immunology, Trinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland
  2. 2.European Research Centre for Drug Discovery & Development, DBCFUniversity of SienaSienaItaly
  3. 3.West German Cancer Center, Medical OncologyEssenGermany

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